Abstract This proposal seeks funds to translate existing antiretroviral drugs (ARVs) into scalable long acting medicines. A step-wise approach is offered with defined ?go no go? criteria. The first is conversion of nucleoside reverse transcriptase and an integrase inhibitor(s) into lipophilic prodrug nanocrystals. These conversions are designed for simple, safe and scalable productions under current good manufacturing practices. Following the production of ARV nanocrystals, the second step will optimize CD4+ T cell uptake while sustaining drug depots in macrophages. ARV release from prodrugs will occur by controlled hydrolysis enabling sustained antiretroviral potency. The third will facilitate distribution of prodrug nanocrystals into lymphoid, gut associated lymphoid tissue, genitourinary and central nervous system tissues. The fourth, will complete tests designed to limit off target toxicity (S Cohen) by screening pro-, native- and nanocrystal- drug formulations in cell and tissue assays. These extended toxicology tests will serves to investigate any or no adverse events that follow increased ARV levels in cells and tissues. Our goal is the production of safe well-tolerated long acting slow effective release antiretroviral therapies with ?putative? dosing intervals of up to once every six months. The design will offer maximal effectiveness for pre-exposure prophylaxis and treatment regimens. The specific aims are supported by extensive published data sets. To accomplish the proposed research, a partnership was made between a medicinal and polymer chemist (B Edagwa) and a virologist, cell biologist, and immunologist (H Gendelman). This collaboration will accelerate transformation of short- to long-acting ARVs. Biological testing will follow product development in cell and animal models. Formulation safety will be realized by continuous testing of replicate short-acting native ARV formulations in good laboratory and current good manufacturing practice facilities. The pathway for ARV nanocrystal development will move forward by sequential Go No Go criteria. Drug choices, formulation stability, drug combinations, tissue and cell targeting, toxicology, pharmacokinetics (PK), and pharmacodynamics (PD) profiles follow the action plan. Several have ?reached? drug manufacture. The outcome of these experiments can reduce drug toxicities, improve regimen adherence, and provide enhanced viral prevention into tissue reservoirs. The research builds on an already strong track record in cell-targeted nanomedicines. Antiretroviral responses and endosomal trafficking will be tested. PK and PD mouse screens (S Gorantla) will validate the findings. Overall, our long-term goal is to transform existing antiretroviral treatment regimens into long acting therapies.